Intermolecular reactions amide arylation

In addition to amines, some derivatives of amines can be arylated. Weakly basic amides are arylated, and intermolecular reactions between aryl bromides and tri-flates 48 with benzamide can be carried out. Combined uses of xantphos (IX-IO) and CS2CO3 in THF or dioxane gave the most successful results. The cyclic urea 49 was diarylated [40]. Sulfonamides are also arylated [41]. Intramolecular reaction of the secondary amides such as 50 or carbamates offers convenient synthetic methods for five-, six-, and seven-membered lactams like 51. As ligands, MOP (VI-12), DPEphos (IX-9), xantphos (IX-IO), and BINAP are used depending on the size of the rings. As an example, ligand IX-9 is the most suitable for the preparation of the five-membered A-carbobenzyloxy derivative 52a from 52, but BINAP was not effective. 

The intermolecular coupling of lactams and acyclic amides has also been reported. Reactions of carbamates with aryl halides occurred in the presence of catalysts ligated by P(/-Bu)3.78 Both carbamates and amides coupled with aryl halides in the presence of a catalyst bearing Xantphos.90 In addition, the coupling of lactams with aryl halides has been successful. A combination of Pd(OAc)2 and DPPF first formed A-aryl lactams in good yields from 7-lactams, but the arylation of amides was improved significantly by the use of Xantphos (Equations (20) and (21)).90 91 The reaction of aryl halides with vinyligous amides has also been reported 92... 

One of our initial forays into Mo(CO)6-promoted carbonylations included the investigation of intermolecular reactions using amines as nucleophiles to form secondary and tertiary aromatic amides from aryl bromides and iodides [27]. Subsequent work using the activating preligand f-Bu3PHBF4 has allowed for the extension of this chemistry into examples using aryl chlorides as substrates (Scheme 1) [30]. 

Prior to the recent paper by Buchwald, an intermolecular version of the arylation of carbamates was published by Hartwig et al. (Eq. (22)) [163]. His group showed that reactions catalyzed by a combination of Pd(OAc)2 and P(tBu)3 formed N-aryl carbamates from aryl bromides or chlorides and tert-butyl carbamate, but that this system was inactive for reactions of amides or sulfonamides. Again, the reaction conditions were not as mild as those used for animation, but they were similar to those employed in the reactions with Xantphos. For the intermolecular reactions, the use of sodium phenoxide as base was crucial. 

Hi. Intermolecular reactions of carbamates. Carbamates possess a more electron-rich nitrogen atom than amides or sulfonamides, and thus participate more readily in palladium-catalyzed aminations of aryl halides. For example, f-butyl carbamate has been shown to react with aryl halides to form f-Boc protected anilines (equation 34)68. The catalyst... 

Amides. Despite many investigations in the 1970s and 1980s on Pd-catalyzed a-arylation of carboxylic acid derivatives, that of amides had not been studied until recently. In 1998, the reaction of potassium enolates of 7V,7V-dimethylacetamide (DMA) and other amides with aryl bromides in the presence of catalytic amounts of Pd(dba)2 and bidentate phosphines, such as BINAP and dppf, was shown to provide the desired a-arylated products in up to roughly 70% yields, as shown in Table Diarylation competed with monoaryladon to the extent of up to 18%. Under the conditions used, the intermolecular reactions of amides other than acetamides were rather disappointing, as indicated by the last two entries in Table 5. Clearly, additional development is desirable. Its intramolecular cyclic version, however, is considerably more favorable, as discussed in the following subsection. 

No intermolecular reactions of acyclic sulfonamides or amides with aryl halides have been reported, but the arylation of lactams has been published. Shakespeare showed that a combination of Pd(OAc)2 and DPPF formed N-aryllactams in good yields when using five-membered lactams (Eq. 29). Reaction times were long for couplings involving... 

Carbamates possess a more electron-rich nitrogen than amides or sulfonamides, and the intermolecular reaction of t-butylcarbamate with aryl halides to form t-Boc-protected anilines has been realized (Eq. 30). As one might expect from the increased rates for amine and indole arylation using the Pd(dba)2/P(t-Bu)3 catalyst, it is this system that allows for the arylation of i-butylcarbamate. Reaction of other carbamates, such as methyl or benzyl carbamate and oxazolinone, occurred in lower yield. However, reaction of t-butyl carbamate with bromoarenes occurred at 100 °C in yields ranging from 62% to 86% with electron-rich, electron-neutral, and sterically hindered or unhindered bromoarenes. Reactions of chloroarenes were again slower, but did occur at 130 °C to give Boc-protected aniline in 59% yield for reaction of chlorotoluene. 

With respect to the substrate scope, ketones are the most efficient nucleophiles although the intermolecular reaction works also well for esters, amides and Weinreb amides (Fig. 2.7). Regarding the Michael acceptor, enones are the best electrophiles with a wide range of substituents tolerated (alkyl, aryl and heteroaryl ketones). a,p-Unsaturated esters, in the case of the intermolecular cyclopropanation, and a,p-unsaturated diimides for the intramolecular reaction, extends the substrate scope of the process (Fig. 2.7). A transition state model for the intramolecular cyclopropanation reaction has been proposed as depicted in Scheme 2.38 for catalyst 65 [106d]. In this model the ammonium salt adopts a conformation that gives the Z-enolate of the nucleophile on deprotonation with the base. The intramolecular conjugate addition of the enolate then takes place through a boat-type transition state. 

A Merck research group discovered that the cross-coupling reaction between aryl halides and vinylogous amides could take place under the catalysis of Pd/DavePhos. When 1,2-dibromobenzene was used, a cascade intermolecular C-N bond coupling and intramolecular Heck reaction occurred to provide 2,3-disubstituted indoles (Scheme 2) [25]. 

The last example discussed concerns secondary acyclic amides, known to be poor nucleophilic partners rarely involved in coupling reactions with aryl halides. Recently a procedure (TaUlefer, Monnier et al.) has described a versatile catalytic system allowing their intermolecular N-arylation (Scheme 12) [165]. Overcoming this challenge using a simple copper/diketone (L27) system offers a general method for the preparation of acyclic tertiary amides. The structure-activity relationship studies of these important targets are thus facilitated by this method, which complements the known systems based on palladium. 

Ester and Thioester Formation. These reactions occur through the same O-acylurea or anhydride active intermediate as in the amide coupling reactions, and the discussion of associated problems applies here as well. In general, alkyl and (particularly) aryl thiols can be efficiently coupled to carboxylic acids using DCC. Reactions of primary and secondary alcohols proceed reliably, but require the presence of an acylation catalyst. This is usually 4-Dimethylaminopyridine (DMAP), " (see also 1,3-Dicyclohexylcarbodiimide—4-Dimethylaminopyridine), but others have been used including 4-pyrrolidinopyridine and pyridine (.solvent) with catalytic p-Toluenesulfonic Acid The acylation of more hindered alcohols often re.sults in reduced yields however, even f-butanol can be acylated, providing a useful route to t-butyl esters. Various other carbodiimide derivatives have also been used in the preparation of esters. As with amides, which are not limited to intermolecular reactions, a wide variety of lactones can also be synthesized. ... 

In intermolecular cyclopropanations [100], it was found better to use a-bromoesters and amides as ylide precursors and a,/ -unsaturated ketones and esters as electron-deficient alkenes - rather than using a-haloketones as the ylide precursor. (For experimental details see Chapter 14.11.4). The reaction gives access to a range of 1,2-dicarbonyl-substituted cyclopropanes (see Fig. 10.5). The al-kene could have an aryl-, alkyl- or indole-substituted ketone, and a-substitution was also tolerated. Notably, Weinreb amides could be used as the ylide precursor and the product subsequently transformed into a diketocyclopropane. Both enan-... 

The scope aromatic C-N bond formation extends beyond simple amine substrates. For example, selected imines, sulfoximines, hydrazines, lactams, azoles, and carbamates give useful products from intermolecular aromatic C-N bond formation. Intramolecular formation of aryl amides has been reported. In addition, allylamine undergoes arylation, providing a readily cleaved amine alternative to the ammonia surrogates benzylamine, t-butylcarbamate, or benzophenone imine. Although it is an amine substrate, the reaction of this reagent is included here because of its special purpose. 

More recently, the use of potassium phosphate has also been reported for the a-arylation of ketones with chloroarenes. KHMDS was the most effective base for the intermolecular arylation of A Af-dialkylamides (eq 35). Higher yields were observed with KHMDS compared to LiTMP. Use of NaOr-Bu resulted in low conversion together with a high level of undesired side products, while LDA appeared to deactivate the system. Coupling of unfunctionalized and electron-rich aryl bromides with A,A-dimethylacetainide afforded a-aryl amides in moderate to good yields when the reaction was conducted with at least 2 equiv of KHMDS base. Diarylation of acetamides as well as hydro-dehalogenation of the aryl halides were side reactions that limited this process. 

Productive foldamer research requires foldamers with certain backbone characteristics. The backbone must be stable, easily synthesized and have some degree of flexibility. It is also helpful to have a well-characterized conformational profile, known intermolecular interactions (such as H-bonding), and good handling characteristics, such as solubility. As shown in Tables 44.1 and 44.2, a wide variety of bond forming reactions have been used to build foldamers. The most popular, by far, is the amide bond however, other chemistry highlights include ureas, phosphate esters, ethers, aryl ethynylenes, biphenyls, and pyridines. 

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